© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
BRCA1 and the Cellular Response to Chemotherapy
Germline mutations in the BRCA1 gene account for approximately 5% of breast and ovarian cancers, and lower than normal BRCA1 expression may be an important factor contributing to sporadic cancers. BRCA1 responds to damaged DNA by participating in DNA repair pathways, mRNA transcription, cell cycle regulation, and protein ubiquitination. Because most chemotherapeutic agents either directly or indirectly damage DNA, the association between BRCA1 activity and chemotherapy-induced DNA damage has been investigated. Kennedy et al. (p. 1659) review the evidence that the level of BRCA1 function in an individual patient can guide the type of chemotherapy used to treat breast and ovarian cancer. They conclude that current evidence indicates that loss of BRCA1 function in cancers may be associated with sensitivity to DNA-damaging chemotherapy and may also be associated with resistance to spindle poisons. They recommend that prospective clinical studies be conducted to investigate the role of BRCA1 in the response to chemotherapy.
Selenium and Colorectal Cancer
Although data from a large randomized clinical trial suggested that selenium intake is associated with a reduction in colorectal cancer risk, studies have not shown a consistent association. Jacobs et al. (p. 1669) analyzed data combined from three randomized nutrition trials to determine the relationship between selenium and colorectal cancer. Quartiles of baseline blood selenium levels were established based on data gathered from 1763 trial participants. Although the association between selenium levels and colorectal cancer risk varied by study, the combined analysis revealed that individuals with selenium levels in the highest quartile had a lower risk of colorectal cancer than those in the lowest quartile. The authors conclude that their data support previous findings that higher selenium status may be associated with a decreased risk of colorectal cancer.
In a related editorial, Duffield-Lillico et al. (p. 1645) note that the results of this pooled analysis are consistent with earlier secondary data from a randomized prevention trial that suggested a reduced risk of colorectal cancer associated with selenium intake. The authors discuss possible biologic mechanisms for this association.
Neoadjuvant Chemotherapy in Head and Neck Cancer
A randomized phase III trial in nonmetastatic stage III or IV head and neck squamous cell carcinoma found no difference in 2-year overall survival between patients who received four cycles of neoadjuvant chemotherapy followed by locoregional treatment (group A) versus patients who received locoregional treatment alone (group B). Zorat et al. (p. 1714) present the long-term results from 237 patients in that trial. Among operable patients, there was no difference in overall survival at 5 or 10 years between the treatment groups. However, among inoperable patients, overall survival at 5 and 10 years was higher for those in group A than for those in group B. The authors conclude that four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer.
In an editorial, Forastiere (p. 1647) summarizes results of other trials that have produced limited data in support of the use of induction chemotherapy in advanced head and neck cancer. She notes that the promising follow-up results reported by Zorat et al. for patients with inoperable disease bolster soon-to-be activated trials of chemoradiotherapy with and without induction chemotherapy.
Docetaxel and Carboplatin in Ovarian Cancer
Chemotherapy with a platinum agent and a taxane (paclitaxel) is the standard of care for ovarian carcinoma. Vasey et al. (p. 1682) compared the docetaxel–carboplatin drug combination with the paclitaxel–carboplatin drug combination as first-line chemotherapy for stage Ic–IV epithelial ovarian cancer in a phase III randomized trial. After a median follow-up of 23 months, they found that both groups had similar progression-free survival, overall survival at 2 years, and objective tumor and CA-125 response rates. The main toxicity differences were neuropathy (worse with paclitaxel) and neutropenia (worse with docetaxel). Global quality of life scores were similar in both groups, but many symptom scores favored docetaxel over paclitaxel. They conclude that, although longer follow-up is required for a definitive result for overall survival, both drug combinations appear to be associated with similar progression-free survival.
Pneumonitis After Paclitaxel and Radiation for Breast Cancer
Because taxane-based chemotherapy has been associated with an increased risk of radiation pneumonitis in patients with breast cancer, Yu et al. (p. 1676) prospectively investigated this association among patients participating in a phase III randomized trial who received either paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC only and who subsequently underwent radiation therapy. They found a very low risk of clinically relevant radiation pneumonitis in patients treated with FAC followed by radiation therapy whether or not paclitaxel was administered. They conclude that for patients treated with sequential chemotherapy and radiation therapy, recommendations for radiation and paclitaxel treatment should not be affected by concerns about the risk of radiation pneumonitis. However, they caution that, if chemotherapy and radiation therapy are given concurrently or in close temporal proximity, the association still needs to be clarified.
Methotrexate and EBV-Positive Lymphomas
Patients with rheumatoid arthritis or polymyositis who are treated with the immunosuppressant methotrexate (MTX) have an increased risk of developing Epstein–Barr virus (EBV)-positive lymphomas compared with patients treated with other immunosuppressants. To investigate the mechanism of this effect, Feng et al. (p. 1691) analyzed EBV infection and gene expression in EBV-positive cells treated with MTX and other drugs. They found that MTX induced the expression of lytic viral gene expression in latently infected cells. Moreover, a complete viral replication cycle occurred in MTX-treated cells that resulted in the release of infectious virions. Patients treated with MTX similarly had higher EBV viral loads than patients treated with other immunosuppressive regimens. The authors suggest that the association between MTX treatment and EBV-positive lymphomas in rheumatoid arthritis and polymyositis patients may reflect the combination of MTX's ability to induce EBV replication and its immunosuppressive effects.
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